Synthesis and Evaluation of a Macrocyclic Actinium-225 Chelator, Quality Control and In Vivo Evaluation of 225 Ac-crown-αMSH Peptide.

Targeted alpha-therapy (TAT) has great potential for treating a broad range of late-stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium-225 (225 Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named 'crown', which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized 225 Ac-crown-αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of 225 Ac-crown-αMSH showed favorable tumor-to-background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of 225 Ac-crown-αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.

Combined Effects of Confinement and Macromolecular Crowding on Protein Stability.

Confinement and crowding have been shown to affect protein fates, including folding, functional stability, and their interactions with self and other proteins. Using both theoretical and experimental studies, researchers have established the independent effects of confinement or crowding, but only a few studies have explored their effects in combination; therefore, their combined impact on protein fates is still relatively unknown. Here, we investigated the combined effects of confinement and crowding on protein stability using the pores of agarose hydrogels as a confining agent and the biopolymer, dextran, as a crowding agent. The addition of dextran further stabilized the enzymes encapsulated in agarose; moreover, the observed increases in enhancements (due to the addition of dextran) exceeded the sum of the individual enhancements due to confinement and crowding. These results suggest that even though confinement and crowding may behave differently in how they influence protein fates, these conditions may be combined to provide synergistic benefits for protein stabilization. In summary, our study demonstrated the successful use of polymer-based platforms to advance our understanding of how in vivo like environments impact protein function and structure.

Loading capacity of CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants with different cements.

OBJECTIVE: This study evaluated the loading capacity of CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants with different cements. MATERIAL AND METHODS: Fifty one-piece zirconia implants were embedded in epoxy resin. The abutment aspect of one implant was optically scanned and a standardized upper canine was designed with CAD-software. Fifty feldspathic ceramic crowns were milled, polished, and mounted on the implants either without any cement, with a temporary cement or with three different composite resin cements after surface pretreatment as recommended by the manufacturers (n = 10). After storage in distilled water at 37°C for 24 hr, specimens were loaded until fracture on the palatal surface of the crown at an angle of 45° to the long axis of the implant and loads until fracture were detected and compared. Compressive strength of the investigated cement materials was determined. Statistical analyses were done with One-way ANOVA followed by post hoc Fisher LSD test (α = 0.05). RESULTS: The cements revealed significantly different compressive strength values (temporary cement: 37.1 ± 7.0 MPa; composite resin cements: 185.8 ± 21.3, 277.9 ± 22.1, and 389.0 ± 13.6 MPa, respectively). Load-at-fracture values had an overall mean value of 237.1 ± 58.2 N with no significant difference among the composite resin cements (p > 0.05). Fracture load values with the temporary cement or without cement were significantly lower (p < 0.002). CONCLUSIONS: CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants provide sufficient resistance to intraoral forces.

Pillar-Shaped Macrocyclic Hosts Pillar[n]arenes: New Key Players for Supramolecular Chemistry.

In 2008, we reported a new class of pillar-shaped macrocyclic hosts, known as "pillar[n]arenes". Today, pillar[n]arenes are recognized as key players in supramolecular chemistry because of their facile synthesis, unique pillar shape, versatile functionality, interesting host-guest properties, and original supramolecular assembly characteristics, which have resulted in numerous electrochemical and biomedical material applications. In this Review, we have provided historical background to macrocyclic chemistry, followed by a detailed discussion of the fundamental properties of pillar[n]arenes, including their synthesis, structure, and host-guest properties. Furthermore, we have discussed the applications of pillar[n]arenes to materials science, as well as their applications in supramolecular chemistry, in terms of their fundamental properties. Finally, we have described the future perspectives of pillar[n]arene chemistry. We hope that this Review will provide a useful reference for researchers working in the field and inspire discoveries concerning pillar[n]arene chemistry.

Luminescent properties of 4-aminobenzo-15-crown-5 after preferential binding of ferric ions in aqueous solutions.

We report a combined approach that introduces the use of 4-aminobenzo-15-crown-5 (4AB15C5) for the detection of ferric(III) ions by colorimetric, ultraviolet (UV)-visible light absorption, fluorescence, and live-cell imaging techniques along with density functional theory (DFT) calculations. We have found that 4AB15C5 is sensitive and selective for binding ferric(III) ions in aqueous solutions. DFT calculations using the polarizable continuum model have been used to explain the strong binding of the ferric ion by 4AB15C5 in aqueous solutions. The detection limit in the fluorescence quenching measurements was found to be as low as 50 µM for the ferric ion with a determined Stern-Volmer constant of 1.52 × 104  M-1 . Fluorescence intensity did not change for other ions tested, Fe2+ , Co2+ , Mn2+ , Mg2+ , Zn2+ , Ca2+ , NH4+ , Na+ , and K+ ions. Live-cell fluorescence imaging was also used to check the intracellular variations in ferric ion levels. Our spectroscopic data indicated that 4AB15C5 can bind ferric ions selectively in aqueous solutions.

Antibiotic Potency against E.†coli Is Enhanced by Channel-Forming Alkyl Lariat Ethers.

Several N,N'-bis(n-alkyl-4,13-diaza[18]crown-6) lariat ethers were found to significantly enhance the potency of rifampicin and tetracycline, but not erythromycin and kanamycin, against the non-pathogenic DH5α and K-12 strains of Escherichia coli when administered at levels below their minimum inhibitory concentrations (MICs). The enhancements in antibiotic potency observed for the lariat ethers ranged from three- to 20-fold, depending on the strain of E. coli, the antibiotic, and the lengths of the alkyl chains attached at the macroring nitrogen atoms. The dialkyl lariat ethers, previously thought to only be cation carriers, formed well-behaved, ion-conducting pores in soybean asolectin membranes, as judged by planar bilayer conductance measurements. The ability of lariat ethers to form stable pores, which appeared to be aggregated, depended in part on alkyl chain length and in part on the composition of the bilayer membrane in which they were studied.

Cesium cation templated selective synthesis of a "cone-shaped" sugar macrotricyclic cryptand: A dual anion-cation molecular recognition of potassium tartrate.

Cesium templated Staudinger-aza-Wittig tandem reaction (S.A.W.) has been used in the synthesis of a bis-diazacrown-bis-cellobiosyl-tetra-ureido cryptand. A novel macrotricyclic compound having a "cone-shaped" configuration was selectively obtained. Additionally, first results on potential recognition properties of the cryptand are also given.

Engineered Ionic Gates for Ion Conduction Based on Sodium and Potassium Activated Nanochannels.

In living systems, ion conduction plays a major role in numerous cellular processes and can be controlled by biological ion channels in response to specific environmental stimuli. This article describes biomimetic ionic gates for ion conduction based on sodium and potassium activated nanochannels. The Na(+) activated ionic gate and K(+) activated ionic gate were developed by immobilizing the alkali metal cation-responsive functional molecules, 4'-aminobenzo-15-crown-5 and 4'-aminobenzo-18-crown-6, respectively, onto the conical polyimide nanochannels. When the ionic gate was in the presence of the specific alkali metal cation, positively charged complexes formed between the crown ether and the alkali metal cation. On the basis of the resulting changes in surface charge, wettability and effective pore size, the nanochannel can achieve reversible switching. The switching behaviors of the two complexes differed due to the differences in binding strength between the two complexes. The Na(+) activated ionic gate is able to open and close to control the ion conduction through the nanochannel, and the K(+) activated ionic gate enables selective cation and anion conduction through the nanochannel. The Na(+) and K(+) activated ionic gates show great promise for use in clinical medicine, biosensors and drug delivery based on their high sensitivity and selectivity of being activated, and good stability.

A thermodynamic insight into the recognition of hydrophilic and hydrophobic amino acids in pure water by aza-scorpiand type receptors.

Interactions of different hydrophilic (His, Asp, Glu,) and hydrophobic (Ala, Phe, Tyr, Trp) amino acids in water with a scorpiand aza-macrocycle (L1) containing a pyridine group in the ring and its derivative (L2) bearing a naphthalene group in the tail have been analysed by potentiometric and calorimetric measurements. Theoretical calculations corroborate that major attractive forces that hold the adduct together are hydrogen bonds and salt-bridges, even though other interactions such as π-stacking or NH(+)⋯π may contribute in the case of hydrophobic amino acids and L2. Calorimetric measurements indicate that the interactions between L1 and the different amino acids are principally driven by entropy, often associated with solvation/desolvation processes.

[Research progress of the drug delivery system of antitumor platinum drugs with macrocyclic compounds].

Platinum-based anticancer drugs have been becoming one of the most effective drugs for clinical treatment of malignant tumors for its unique mechanism of action and broad range of anticancer spectrum. But, there are still several problems such as side effects, drug resistance/cross resistance and no-specific targeting, becoming obstacles to restrict its expanding of clinical application. In recent years, supramolecular chemistry drug delivery systems have been gradually concerned for their favorable safety and low toxicity. Supramolecular macrocycles-platinum complexes increased the water solubility, stability and safety of traditional platinum drugs, and have become hot focus of developing novel platinum-based anticancer drugs because of its potential targeting of tumor tissues/organs. This article concentrates in the research progress of the new drug delivery system between platinum-based anticancer drugs with three generations of macrocycles: crown ether, cyclodextrin, cucurbituril and calixarene.

Homochiral columns constructed by chiral self-sorting during supramolecular helical organization of hat-shaped molecules.

A library of dendronized cyclotriveratrylene (CTV) crowns substituted with chiral, racemic, or achiral peripheral alkyl chains, including enantiopure R and S branched alkyls, "racemic by mixture", "racemic by synthesis", n-octyl, and n-dodecyl groups was synthesized. In solvophobic solvents and in bulk they self-assemble in helical columns. Their solution and bulk shape-persistent supramolecular structures were determined by a complementary combination of circular dichroism (CD) and UV in solution and thin film, microspot CD in thin film, differential scanning calorimetry combined with fiber X-ray diffraction, computer simulation, and molecular models. In solution, self-assembly via a cooperative mechanism generates single-handed columns from enantiopure CTVs and mixtures of right- and left-handed columns from racemic by mixture, racemic by synthesis, other combinations of R and S, and even from achiral compounds. In bulk state all supramolecular columns form a 3D hexagonal crystalline phase, Φ(h)(k) (P63 symmetry), that can be obtained only from single-handed columns and a columnar hexagonal 2D liquid crystal, Φ(h). The highest order Φ(h)(k) consists of enantiopure single-handed columns that are slightly distorted 12-fold triple helices. The "hat-shaped" dendronized CTV assembles in bent-branch pine-tree columns that allow interdigitation of alkyl groups in adjacent columns regardless of their direction. Enantiomerically rich, racemic, and achiral compositions undergo deracemization in the crystal state by transfer of the transient disc-like conformer of dendronized CTV from column to column during crown inversion. Solid state NMR experiments identified motional processes that allow such transfer. This unprecedented supramolecular chiral self-sorting will impact the creation of functions in complex systems.

Understanding spin structure in metallacrown single-molecule magnets using magnetic compton scattering.

The 3d-4f mixed metallacrowns frequently show single-molecule magnetic behavior. We have used magnetic Compton scattering to characterize the spin structure and orbital interactions in three isostructural metallacrowns: Gd2Mn4, Dy2Mn4, and Y2Mn4. These data allow the direct determination of the spin only contribution to the overall magnetic moment. We find that the lanthanide 4f spin in Gd2Mn4 and Dy2Mn4 is aligned parallel to the Mn 3d spin. For Y2Mn4 (manganese-only spin) we find evidence for spin delocalization into the O 2p orbitals. Comparing the magnetic Compton scattering data with SQUID studies that measure the total magnetic moment suggests that Gd2Mn4 and Y2Mn4 have only a small orbital contribution to the moment. In contrast, the total magnetic moment for Dy2Mn4 MCs is much larger than the spin-only moment, demonstrating a significant orbital contribution to the overall magnetic moment. Overall, these data provide direct insight into the correlation of molecular design with molecular magnetic properties.

A pH-sensitive peptide-containing lasso molecular switch.

The synthesis of a peptide-containing lasso molecular switch by a self-entanglement strategy is described. The interlocked rotaxane molecular machine consists of a benzometaphenylene[25]crown-8 (BMP25C8) macrocycle surrounding a molecular axle. This molecular axle contains a tripeptidic sequence and two molecular stations: a N-benzyltriazolium and a pH-sensitive anilinium station. The tripeptide is located between the macrocycle and the triazolium station, so that its conformation can be tailored depending on the shuttling of the macrocycle from one station to the other. At acidic pH, the macrocycle resides around the anilinium moiety, whereas it shuttles around the triazolium station after deprotonation. This molecular machinery thus forces the lasso to adopt a tightened or a loosened conformation.

Oxothiomolybdenum derivatives of the superlacunary crown heteropolyanion {P8W48}: structure of [K4{Mo4O4S4(H2O)3(OH)2}2(WO2)(P8W48O184)]30­ and studies in solution.

Reaction of the cyclic lacunary [H(7)P(8)W(48)O(184)](33-) anion (noted P(8)W(48)) with the [Mo(2)S(2)O(2)(H(2)O)(6)](2+) oxothiocation led to two compounds, namely, [K(4){Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2)(WO(2))(P(8)W(48)O(184))](30-) (denoted 1) and [{Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2)(P(8)W(48)O(184))](36-) (denoted 2), which were characterized in the solid state and solution. In the solid state, the structure of [K(4){Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2)(WO(2))(P(8)W(48)O(184))](30-) reveals the presence of two disordered {Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2+) "handles" connected on both sides of the P(8)W(48) ring. Such a disorder is consistent with the presence of two geometrical isomers where the relative disposition of the two {Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2+) handles are arranged in a perpendicular or parallel mode. Such an interpretation is fully supported by (31)P and (183)W NMR solution studies. The relative stability of both geometrical isomers appears to be dependent upon the nature of the internal alkali cations, i.e., Na(+) vs K(+), and increased lability of the two {Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2+) handles, compared to the oxo analogous, was clearly identified by significant broadening of the (31)P and (183)W NMR lines. Solution studies carried out by UV-vis spectroscopy showed that formation of the adduct [{Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2)(P(8)W(48)O(184))](36-) occurs in the 1.5-4.7 pH range and corresponds to a fast and quantitative condensation process. Furthermore, (31)P NMR titrations in solution reveal formation of the "monohandle" derivative [{Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(P(8)W(48)O(184))](38-) as an intermediate prior to formation of the "bishandle" derivatives. Furthermore, the electrochemical behavior of [{Mo(4)O(4)S(4)(H(2)O)(3)(OH)(2)}(2)(P(8)W(48)O(184))](36-) was studied in aqueous medium and compared with the parent anion P(8)W(48).

The role of conformational changes in the signal enhancement of a selective chemosensor of Pb2+.

In this work, the complexes formed by a fluoroionophore with three dications (M(2+) = Ca(2+), Hg(2+) and Pb(2+)) were studied theoretically, by applying both Density Functional Theory and its Time Dependent version (TDDFT). The experimental information concerning this fluoroionophore-Pb(2+) complex indicates a large increment in the absorption and emission signals. From a theoretical point of view, by using the structure with minimum energy of the fluoroionophore free as reference; distortions in the structure are observed when the complexes are formed and consequently important changes in terms of certain properties occur. Although there are increments in signal intensity in the case of the three ions considered here, TDDFT predicts that the Pb(2+) complex will manifest the most pronounced response and this conforms to experimental observations. Thus, we can associate the experimentally observed behavior with conformational changes. In order to corroborate this hypothesis we have analyzed the fluoroionophore-M(2+) structure complexes, both with ions, without ions and without the ionophore (which binds the ions); it is evident that if the ligand manifests geometric distortions, then the absorption signal will increase. The inert pair effect induces the particular conformation of the complex, when the Pb(2+) is present, acting as a lone pair, which is revealed when the electron localization function is analyzed. If structural distortions are present then the charge distribution and consequently the dipolar moment also present significant changes.

A molecular leverage for helicity control and helix inversion.

The helical tetranuclear complex [LZn(3)La(OAc)(3)] having two benzocrown moieties was designed and synthesized as a novel molecular leverage for helicity control and helix inversion. Short alkanediammonium guests H(3)N(+)(CH(2))(n)NH(3)(+) (n = 4, 6, 8) preferentially stabilized the P-helical isomer of [LZn(3)La(OAc)(3)], while the longer guest H(3)N(+)(CH(2))(12)NH(3)(+) caused a helix inversion to give the M-helical isomer as the major isomer. The differences in the molecular lengths were efficiently translated into helical handedness via the novel molecular leverage mechanism using the gauche/anti conversion of the trans-1,2-disubstituted ethylenediamine unit.

Hydrogen-bond-mediated self-assembly of 26-membered diaza tetraester crowns of 3,5-disubstituted 1H-pyrazole. Dimerization study in the solid state and in CDCl3 solution.

By using an improved synthetic method reported earlier, the cyclic stannoxanes obtained from RN-diethanolamine (R = Me, Bu) and dibutyltin oxide have been reacted with 1H-pyrazole-3,5-dicarbonyl dichloride to afford 26-membered diaza tetraester crowns (1, R = Me; 3, R = Bu) and 39-membered triaza hexaester crowns (2, R = Me; 4, R = Bu). The new structures were identified from their analytical and spectroscopic ((1)H and (13)C NMR, FAB-MS, and/or ESI-MS) data. Both diaza tetraester crowns (1 and 3), containing two 1H-pyrazole units, self-assemble into dimeric species through the formation of four hydrogen bonds involving the two NH pyrazole groups and the two tertiary amine groups of both crowns, as proved by X-ray crystallography and NMR analysis. Preliminary NMR, ESI-MS, MALDI-TOF-MS, and molecular modeling studies suggest that, in CDCl(3) solution, 1 interacts with ethyleneurea (ETU), affording 1:1, 2:1, and 2:2 1-ETU complexes.

Antileukemic activity and cellular effects of rhodium(III) crown thiaether complexes.

The cytostatic properties of novel rhodium(III) thiacrown ether complexes [RhCl(LL)([9]aneS(3))](n+) with either aromatic κ(2)N ligands (n = 2) or anionic chelate ligands (n = 1) have been investigated for the human cancer cell lines HT-29 and MCF-7 and for immortalized HEK-293 cells. Taken together with literature IC(50) values for analogous complexes with polypyridyl ligands or 1,4-dithiane, the in vitro assays indicate that dicationic complexes with soft κ(2)N (imino) or κ(2)S (thiaether) ligands exhibit significantly higher antiproliferative effects than those with hard κ(2)N (amino) ligands. Dicationic complexes are more active than monocationic complexes with similar ligands. Pronounced apoptosis-inducing properties towards Jurkat cells were established for complexes with LL = bpm, dpq, and 1,4-dithiane. The order of activity (bpm > 1,4-dithiane > dpq > bpy) contrasts to that observed for adhesive cancer cells (bpm > bpy, 1,4-dithiane > dpq). Necrosis is insignificant in all cases. The percentage of Jurkat cells exhibiting apoptosis after 24 or 48 h incubation periods is directly correlated to the percentage of cells exhibiting high levels of reactive oxygen species. As established by online monitoring with a sensor chip system, treatment of MCF-7 cells with the bpm and 1,4-dithiane complexes leads to a significant and permanent concentration-dependent decrease in oxygen consumption and cellular adhesion.

Molecular assembly of multi-wall carbon nanotubes with amino crown ether: synthesis and characterization.

Synthetic methodology and physicochemical characterization of multi-wall carbon nanotubes (MWCNTs) functionalized with a crown ether molecule is reported. The MWCNTs were synthesized by spray pyrolysis technique using toluene as carbon source and ferrocene as catalyst. The nanotubes were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Oxidation of MWCNTs was carried out by 8 h of sonication in a mixture of sulfuric and nitric acid (3:1). The MWCNT-COOH was amidated with 4-aminobenzo-15-crown-5 under mild reaction conditions using N,N'-dicyclohexylcarbodiimide and dimethylaminopyridine as catalyst and dimethylformamide as solvent, at room temperature for 24 h. The amidation product was characterized by scanning electron microscopy, infrared spectroscopy, X-ray photoelectron spectroscopy, atomic force microscopy and a mass spectrometry study to determine the fragmentation pattern being m/z 309, 177 and 149 the most important ions.

Synthesis and chelation study of a fluoroionophore and a glycopeptide based on an aza crown iminosugar structure.

Capitalizing on a recently reported iminosugar-based aza-crown (ISAC) accessed by a double Staudinger azaWittig coupling reaction, we have expanded the structural diversity of this new family of sweet cyclam analogs. Replacement of the two secondary amines linking the iminosugar units by two amide bonds obtained a cyclodimerization by with BOP and DIPEA led to a macrocycle that did not demonstrate efficient Zn2+ chelation unlike the parent ISAC. Introduction of two pyrene moieties on the secondary amines of the parent ISAC yielded a new fluoroionophore that selectively binds Hg2+ in methanol.